US11384156B2ActiveUtilityA1

Adoptive T-cell therapy using EMPD-specific chimeric antigen receptors for treating IgE-mediated allergic diseases

77
Assignee: THE NEMOURS FOUNDPriority: Jul 25, 2016Filed: Jul 17, 2017Granted: Jul 12, 2022
Est. expiryJul 25, 2036(~10 yrs left)· nominal 20-yr term from priority
Inventors:Zhengyu Ma
C12N 15/11C12N 2800/00C12N 2510/00C07K 16/4291C07K 2317/34C07K 16/28C07K 2319/03A61P 37/08C07K 2317/622C07K 16/00C07K 2317/24C07K 2319/33C07K 2317/73A61K 2039/505G02F 1/09
77
PatentIndex Score
2
Cited by
44
References
26
Claims

Abstract

A chimeric antigen receptor specific for the extracellular membrane-proximal domain (EMPD) of membrane-bound IgE (mIgE) is provided. The EMPD-specific chimeric antigen receptor comprises an extracellular ligand binding domain capable of binding EMPD, a transmembrane domain, and an intracellular domain that mediates T cell activation upon EMPD binding. Nucleic acids and vectors encoding the EMPD-specific chimeric antigen receptor are provided. T cells transduced with such vectors find use in chimeric antigen receptor-based adoptive T-cell therapy for targeting IgE-expressing B cells and treating IgE-mediated allergic diseases.

Claims

exact text as granted — not AI-modified
I claim: 
     
       1. An EMPD-specific chimeric antigen receptor comprising an extracellular ligand binding domain capable of binding an epitope of membrane-bound IgE extracellular membrane-proximal domain (EMPD), a transmembrane domain, and an intracellular domain that mediates T cell activation upon binding of EMPD to the extracellular ligand binding domain, wherein:
 (1) the extracellular ligand binding domain comprises a single chain Fv fragment comprising a light chain variable region comprising the complementarity determining regions SEQ ID NO: 37, Trp-Ala-Ser, and SEQ ID NO: 38, and a heavy chain variable region comprising the complementarity determining regions SEQ ID NO: 39, SEQ ID NO: 40, and SEQ ID NO: 41, said variable light chain and variable heavy chain being connected by a sequence of amino acids forming a flexible linker; 
 (2) the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 22; and 
 (3) the intracellular domain comprises the amino acid sequence of SEQ ID NO: 50 and the amino acid sequence of SEQ ID NO: 12. 
 
     
     
       2. The EMPD-specific chimeric antigen receptor of  claim 1 , wherein the intracellular domain further comprises a costimulatory signaling domain comprising at least one amino acid sequence selected from the group of SEQ ID NO: 21, SEQ ID NO: 17, SEQ ID NO: 20, and SEQ ID NO: 19. 
     
     
       3. The EMPD-specific chimeric antigen receptor of  claim 2 , wherein the costimulatory signaling domain comprises the amino acid sequence SEQ ID NO: 17. 
     
     
       4. The EMPD-specific chimeric antigen receptor of  claim 1  comprising an amino acid sequence selected from the group of amino sequences consisting of:
 (a) SEQ ID NO:9; and 
 (b) the sequence of amino acids from amino acid 23 to amino acid 554 of SEQ ID NO:9. 
 
     
     
       5. An isolated nucleic acid sequence encoding the EMPD-specific chimeric antigen receptor of  claim 1 . 
     
     
       6. The isolated nucleic acid according to  claim 5 , wherein the encoded intracellular domain further comprises a costimulatory signaling domain comprising at least one amino acid sequence selected from the group of SEQ ID NO: 21, SEQ ID NO: 17, SEQ ID NO: 20, and SEQ ID NO: 19. 
     
     
       7. The isolated nucleic acid according to  claim 6 , wherein the encoded costimulatory signaling domain comprises the amino acid sequence SEQ ID NO: 17. 
     
     
       8. The isolated nucleic acid according to  claim 5 , wherein the EMPD-specific chimeric antigen receptor comprises an amino acid sequence selected from the group of amino sequences consisting of:
 (a) SEQ ID NO: 9; and 
 (b) the sequence of amino acids from amino acid 23 to amino acid 554 of SEQ ID NO: 9. 
 
     
     
       9. The isolated nucleic acid sequence according to  claim 8 , comprising a nucleic acid sequence selected from the group consisting of:
 (a) SEQ ID NO: 8; and 
 (b) the sequence of nucleotides from nucleotide 67 to nucleotide 1662 of SEQ ID NO: 8. 
 
     
     
       10. A vector comprising a nucleic acid sequence encoding the EMPD-specific chimeric antigen receptor of  claim 1 . 
     
     
       11. The vector according to  claim 10 , wherein the EMPD-specific chimeric antigen receptor comprises an amino acid sequence selected from the group of amino sequences consisting of:
 (a) SEQ ID NO: 9; and 
 (b) the sequence of amino acids from amino acid 23 to amino acid 554 of SEQ ID NO: 9. 
 
     
     
       12. The vector according to  claim 11 , comprising a nucleic acid sequence selected from the group consisting of:
 (a) SEQ ID NO: 8; and 
 (b) the sequence of nucleotides from nucleotide 67 to nucleotide 1662 of SEQ ID NO: 8. 
 
     
     
       13. A T cell comprising a nucleic acid sequence encoding the EMPD-specific chimeric antigen receptor of  claim 1 . 
     
     
       14. A T cell expressing the EMPD-specific chimeric antigen receptor of  claim 1 . 
     
     
       15. The T cell of  claim 14 , wherein the intracellular domain further comprises a costimulatory signaling domain comprising at least one amino acid sequence selected from the group of SEQ ID NO: 21, SEQ ID NO: 17, SEQ ID NO: 20, and SEQ ID NO: 19. 
     
     
       16. The T cell of  claim 15 , wherein the costimulatory signaling domain comprises the amino acid sequence SEQ ID NO: 17. 
     
     
       17. An EMPD-binding antibody or antigen binding fragment thereof comprising a light chain variable region the complementarity determining regions SEQ ID NO: 37, Trp-Ala-Ser, and SEQ ID NO: 38, and a heavy chain variable region comprising the complementarity determining regions SEQ ID NO: 39, SEQ ID NO: 40, and SEQ ID NO: 41. 
     
     
       18. The T cell of  claim 14 , wherein the EMPD-specific chimeric antigen receptor comprises an amino acid sequence selected from the group of amino sequences consisting of:
 (a) SEQ ID NO:9; and 
 (b) the sequence of amino acids from amino acid 23 to amino acid 554 of SEQ ID NO: 9. 
 
     
     
       19. The EMPD-binding antibody or antigen binding fragment thereof of  claim 17 , wherein the antibody or antigen binding fragment thereof is humanized. 
     
     
       20. The EMPD-binding antibody or antigen binding fragment thereof of  claim 17 , wherein said antibody or antigen binding fragment thereof is an scFv and said variable light chain and variable heavy chain are connected by a sequence of amino acids forming a flexible linker. 
     
     
       21. An isolated nucleic acid sequence encoding the EMPD-binding antibody or antigen binding fragment thereof of  claim 17 . 
     
     
       22. An isolated nucleic acid sequence encoding the EMPD-binding antibody or antigen binding fragment thereof of  claim 19 . 
     
     
       23. A host cell expressing the EMPD-binding antibody or antigen binding fragment thereof of  claim 20 . 
     
     
       24. A fusion polypeptide comprising the EMPD-binding antibody or antigen binding fragment thereof of  claim 17  and a second polypeptide. 
     
     
       25. An isolated nucleic acid sequence encoding the fusion polypeptide of  claim 24 . 
     
     
       26. A host cell expressing the fusion polypeptide of  claim 24 .

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